1. Field
The invention is in the field of immunology, and more specifically, in the field of treating immune systems to reduce the chance of the system attacking beneficial cells. This includes treatments and procedures for reducing the risk of graft versus host disease associated with bone marrow transplantation, diseases associated with organ or other tissue transplants, as well as autoimmune diseases.
2. State of the Art
The cellular immune system in animals, particularly mammals such as human beings, include cells in the blood, such as T-cells, which recognize aberrant cells in the body and attack and destroy such cells. Aberrant cells result, for example, from viral and other infections and cancerous and diseased cells and express one or more abnormal antigens. The aberrant cells are recognized by immune system cells. By recognizing and destroying aberrant cells, a body's cellular immune system kills diseased and other harmful cells and protects the body. However, in some instances (i.e., autoimmune diseases) certain immune system cells attack normal cells. In other instances, such as allogenic bone marrow transplantation, immune system cells attack host cells.
With some cancers, such as leukemia, control of the cancer can only be achieved by treatments such as irradiation or chemotherapy which inadvertently destroy the blood forming cells in the body along with the cancer cells. Bone marrow transplants are done to replace blood forming cells in the body that are destroyed as a result of such treatment. Hematopoietic stem cells are transplanted into the body to form a new immune system. T-cells are part of traditional bone marrow transplants and, since they came from a donor, recognize the host tissue as being foreign, i.e., aberrant, and develop an immune reaction to the antigens on the host cells. This is generally referred to as graft versus host disease (GVHD). Immunosuppressive drugs are used to reduce GVHD. The two main immunosuppressive drugs used over the last two decades are methotrexate and cyclosporin. Although these drugs used alone or in combination decrease the incidence of GVHD, an unacceptable number of patients still die, R. Storb, Transplantation Proceedings, Vol. 27, #5 (October), 1995, pp. 2653-2656. Attempts have been made to prevent GVHD by the removal of T-cells from the donor inoculum with monoclonal antibodies, lectins, or complement lysis so that only stem cells are transplanted. These methods generally reduce the number of T-cells by 1-3 logs and show significant reductions in acute and possibly chronic GVHD. However, since the host is left without a mature cellular immune system for several weeks while the stem cells develop into a new immune system, the success in reducing GVHD is generally associated with an increased risk of infection and relapse of the original malignancy. In addition, secondary tumors such as Epstein-Barr lymphoproliferative disease are likely to appear, C. Anasetti et al., Annu. Rev. Med. 1995, 46:169-179. It is believed that the increased rate of relapse of the original malignancy and possibly the occurrence of secondary tumors is a result of incomplete destruction of the original malignant cells during treatment. The new immune system which develops from the transplant does not recognize the malignant cells as aberrant and thus does not mount an attack. As a result, the few malignant cells that survive treatment are left to grow unchecked by the new immune system. All of these disorders invariably result in death and no improvement in survival rate has yet been realized for patients given T-cell depleted marrow.
With organ or other tissue transplants made into a body having a cellular immune system, the transplant presents foreign tissue to the body. The cellular immune system, recognizing the tissue as made up of foreign or aberrant cells, attacks the transplanted tissue resulting in what is commonly referred to as transplant rejection where the body rejects the transplant. This is also referred to as host versus graft disease (HVGD). Again, in most transplant cases, immunosuppressive drugs are used to inhibit the body's attack on and rejection of the transplant. Since the transplant was probably necessary to save the recipient's life, rejection of the transplant usually results in death. However, use of immunosuppressive drugs to prevent rejection of the transplant generally reduces the ability of the immune system to attack unwanted disease or other harmful cells so the risk of death from disease and infection is increased.
With autoimmune diseases, such as multiple sclerosis, something abnormal happens to a body's cellular immune system and the immune system attacks and destroys the body's own cells. This generally results in death unless the immune system's attack on the body can be controlled. Often, such attacks can be controlled by use of immunosuppressive drugs, however, the success of such control depends upon the disease and the individual. Also, as indicated, use of immunosuppressive drugs reduces the body's ability to fight disease and infection.